Sulfate Reducing Bacteria Induce -Synuclein in Intestinal and Neuronal cells and tissues and Inhibit Tyrosine Hydroxylase in Neuronal cells

Sudha Singh¹Arianne J Capacio¹Cody A Braun¹Amanda Carroll-Portillo²Sephira Ryman^3,4Henry Lin^3,5*

• ¹Biomedical Research Institute of New Mexico, Albuquerque, United States
• ²Internal medicine, The University of New Mexico, Albuquerque, United States
• ³The University of New Mexico, Albuquerque, United States
• ⁴Mind Research Network, Albuquerque, United States
• ⁵New Mexico VA Health Care System, Albuquerque, United States

Parkinson's disease (PD), a synucleopathy characterized by the presence of alpha-synuclein (-syn) aggregates in the brain, is thought to originate in the intestine. Desulfovibrio, resident gut sulfate reducing bacteria (SRB), usually found in very low numbers in a healthy gut, are found in higher numbers in PD. In a recent study, a separate group demonstrated that Desulfovibrio isolated from both PD patients and healthy subjects were fed to C. elegans and were found to increase -syn aggregates in the head region of the worms. How these bacteria induce -syn aggregates in the brain through the gut remain unknown We tested whether Desulfovibrio induced -syn aggregates in the intestinal cells and triggered -syn secretion from these cells into the growth medium and whether this growth medium (devoid of bacteria) further induced -syn aggregates in neurons. We also tested whether Desulfovibrio directly induced -syn aggregates in neuronal cells and inhibited protein expression of tyrosine hydroxylase (TH), a key dopamine-producing enzyme. We also tested whether Desulfovibrio increased -syn levels in intestine, plasma, and in brain in mice. Enteroendocrine STC-1 and neuronal SH-Sy5y cells were infected with Desulfovibrio vulgaris (DSV). We measured -syn aggregation by immunofluorescence. -syn levels in cell culture supernatant (sup), tissues, and plasma were measured by enzyme-linked immunosorbent assay (ELISA). Protein expression of TH and -syn was analyzed by Western blot. We found that DSV increased the number of STC-1cells with -syn aggregates and also induced -syn expression in these cells. Sup from DSV-infected STC-1 had higher -syn levels compared to control uninfected sup and could induce -syn aggregates in SH-Sy5y. DSV also directly induced  syn aggregates and inhibited TH in SH-Sy5y. DSV-gavaged mice had higher levels of -syn in the duodenum, plasma, and in brain and also showed a decreasing trend in TH expression in the brain. Thus, our findings provide a gut-to-brain link tied to the ability of SRB in the gut-to increase expression, aggregation and spread of −syn and decrease of TH in PD.